Scope and Mechanistic Probe into Asymmetric Synthesis of -Trisubstituted--Tertiary Amines by Rhodium Catalysis

Asymmetric reactions that convert racemic mixtures into enantioenriched amines are of significant importance due to the prevalence of amines in pharmaceuticals, with about 60% of drug candidates containing tertiary amines. Although transition-metal catalyzed allylic substitution processes have been developed to provide access to enantioenriched alpha-disubstituted allylic amines, enantioselective synthesis of sterically demanding alpha-tertiary amines with a tetrasubstituted carbon stereocenter remains a major challenge. Herein, we report a chiral diene-ligated rhodium-catalyzed asymmetric substitution of racemic tertiary allylic trichloroacetimidates with aliphatic secondary amines to afford alpha-trisubstituted-alpha-tertiary amines. Mechanistic investigation is conducted using synergistic experimental and computational studies. Density functional theory calculations show that the chiral diene-ligated rhodium promotes the ionization of tertiary allylic substrates to form both anti and syn pi-allyl intermediates. The anti pi-allyl pathway proceeds through a higher energy than the syn pi-allyl pathway. The rate of conversion of the less reactive pi-allyl intermediate to the more reactive isomer via pi-sigma-pi interconversion was faster than the rate of nucleophilic attack onto the more reactive intermediate. These data imply that the Curtin-Hammett conditions are met in the amination reaction, leading to dynamic kinetic asymmetric transformation. Computational studies also show that hydrogen bonding interactions between beta-oxygen of allylic substrate and amine-NH greatly assist the delivery of amine nucleophile onto more hindered internal carbon of the pi-allyl intermediate. The synthetic utility of the current methodology is showcased by efficient preparation of alpha-trisubstituted-alpha-tertiary amines featuring pharmaceutically relevant secondary amine cores with good yields and excellent selectivities (branched-linear >99:1, up to 99% enantiomeric excess).